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Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2662-2670 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.093 Liposome-Encapsulated Doxorubicin in Combination With Standard Agents (cyclophosphamide, vincristine, prednisone) in Patients With Newly Diagnosed AIDS-Related Non-Hodgkin's Lymphoma: Results of Therapy and Correlates of ResponseFrom the Departments of Medicine, Pathology, and Radiology, University of Southern California Keck School of Medicine, Los Angeles, CA; and Elan Corp, Princeton, NJ Address reprint requests to Alexandra M. Levine, MD, Norris Cancer Hospital and Research Institute, 1441 Eastlake Ave, MS-34, Los Angeles, CA 90033; e-mail: alevine{at}usc.edu
PURPOSE: To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. PATIENTS AND METHODS: Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m2 was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. RESULTS: Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm3 (range, 19/mm3 to 791/mm3). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P = .027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism. CONCLUSION: Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.
Patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who are treated with low- or standard-dose chemotherapy and who do not receive highly active antiretroviral therapy (HAART) will, typically, attain complete response (CR) rates of 40% to 50%, with a median survival of approximately 6 months.1-4 The addition of HAART to the therapeutic regimen of such patients has resulted in a substantial increase in median survival, and retrospective analyses have indicated that virologic response to HAART may be the most important factor in predicting both complete remission and/or prolonged survival of affected individuals.5-7 One explanation for the reduced efficacy of standard chemotherapy in patients with AIDS in the absence of HAART relates to the increased incidence of intercurrent opportunistic and/or other infections that may be a direct cause of death, and may also delay subsequent cycles of chemotherapy, leading eventually to treatment failure. The addition of HAART would be expected to reduce the risk of these infections and sequelae.8,9 It has also been hypothesized that suboptimal responses to chemotherapy observed in some patients with AIDS-related lymphoma may be due to tumor cell resistance, mediated by the protein product of MDR-1, p-glycoprotein (P-gp). MDR-1 gene expression has been correlated with clinical resistance to chemotherapy, mediated through overexpression of P-gp, a 170-kd plasma glycoprotein,10-13 which acts as a unidirectional, drug efflux pump, resulting in decreased intracellular drug accumulation.11,12 In lymphoma that is not related to AIDS, the majority of studies have demonstrated MDR-1 expression in fewer than 20% of patients at the time of initial diagnosis,14,15 with an increase to more than 50% at the time of relapse.16 By contrast, in a population of 50 patients with newly diagnosed AIDS-related lymphoma, Tulpule et al demonstrated that tissues from 33 subjects (66%) expressed MDR-1. Of importance, this group had a significantly lower complete remission rate when compared with MDR-1–negative patients.17 Thus, an abnormally high rate of MDR-1 expression in patients with AIDS-NHL may serve as another explanation for the low response rates observed in these individuals. The anthracycline doxorubicin is one of the most active agents in the therapy of patients with aggressive lymphoma. However, doxorubicin is a substrate for P-gp. Myocet (Medeus Pharma Ltd, Herts, UK) is a liposome-encapsulated formulation of doxorubicin, which differs from pegylated liposomal doxorubicin (Doxil; Ortho Biotech Products LP, Raritan, NJ), as well as from unencapsulated, conventional doxorubicin, resulting in an alteration in the pharmacokinetics and biodistribution, with higher area under the curve and smaller volume of distribution, and preferential distribution to liver, spleen, and lymphatics, when Myocet is compared with conventional doxorubicin.18,19 In patients with metastatic breast cancer, Myocet was shown to be associated with a significantly reduced risk of cardiac toxicity, significantly less mucositis, and absence of palmar-plantar erythrodysesthesia, while maintaining antitumor efficacy.20 In vitro studies have demonstrated that liposomal encapsulation of doxorubicin can also overcome excessive drug efflux due to MDR-1 overexpression.21,22 The current prospective phase I/II trial was a dose escalation study undertaken to assess the safety and tolerability of Myocet when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone)23 and used in patients with newly diagnosed AIDS-NHL, all of whom also received HAART. It was also anticipated that preliminary efficacy data would be obtained, as well as data related to correlates of response with respect to MDR-1 protein expression and virologic response to HAART.
Patients Between July 1999 and April 2002, a total of 24 patients were accrued, all of whom had underlying HIV infection, as documented by enzyme-linked immunoabsorbent assay and confirmatory Western blot and/or HIV-1 RNA level in plasma. Patients were required to have newly diagnosed, previously untreated, aggressive non-Hodgkin's lymphoma, including diffuse large cell lymphoma, Burkitt or Burkitt-like lymphoma, anaplastic large cell lymphoma, diffuse mixed lymphoma, high grade T-cell lymphoma, or high-grade lymphoma not otherwise specified. Patients were required to be 18 years of age or older, with a life expectancy of more than 3 months, and a Karnofsky performance status score of 50% or greater. Other eligibility criteria included measurable or evaluable disease. Adequate renal (serum creatinine < 2.0 mg/dL or creatinine clearance at least 60 mL/min), and hepatic function (bilirubin < 2.1 mg/dL, AST < 3x the upper limit of normal) were required, unless abnormalities were due to lymphomatous involvement. Adequate hematologic function (absolute neutrophil count > 1,000/mm3; platelet count > 75,000/mm3) was required, unless secondary to lymphomatous infiltration of the marrow. Left ventricular ejection fraction (LVEF) more than 45% (lower limit of institutional normal range) was also required. Patients with CNS involvement were eligible, provided that systemic lymphomatous disease was also documented. The study was reviewed and approved by the institutional review board of the University of Southern California Keck School of Medicine, and all patients gave signed informed consent before study entry.
Study Evaluation
Treatment
Toxicities and Definition of Maximum-Tolerated Dose
Concomitant Medications
HIV-1 Viral Load and Definition of Viral Control Complete viral control was defined as a 2 log10 or greater decline or undetectable HIV viral load (< 50 copies/mL) at 3 months from start of chemotherapy, or at completion of therapy without subsequent rebound. Transient viral control was defined as a 2 log10 or greater decline in HIV viral load at 3 months from start of chemotherapy, or at completion of therapy, but with rebound. Lack of viral control was defined as a decline of 1 log10 or less, or an increase in HIV viral load.
MDR-1 Determination
Definition of Response to Chemotherapy
Statistical Analyses
A total of 24 patients were accrued, with a median age of 43 years (range, 24 to 61 years). Patient demographic and clinical data are provided in Table 1. Eighteen patients were Hispanic/Latino (75%). Systemic "B" symptoms were present in 15 patients (63%). Serum LDH was elevated in 17 patients (71%), with a median of 282 mg/dL. Pathologic subtypes consisted of diffuse large cell or variants in 19 patients (79%); Burkitt or Burkitt-like lymphoma in two patients (8%), peripheral T-cell lymphoma was present in one patient (4%), and high grade not otherwise specified was seen in two patients (8%). A total of 21 patients (88%) had extranodal disease, and 12 patients (50%) had two or more sites of extranodal lymphoma. Bone marrow was involved in seven patients (29%); liver, in 6 patients (25%); gastrointestinal tract, in 6 patients (25%); and ascites or other effusions were present in three patients (13%). In terms of the age-adjusted International Prognostic Index score,29 four patients (17%) had high-risk disease, 12 patients (50%) had high-intermediate–risk, six patients (25%) had low-intermediate risk features, and two patients (8%) had low-risk disease.
All patients acquired HIV by sexual means, including homosexual contact in 11 (46%), and heterosexual contact in the remainder. History of an AIDS-defining illness before diagnosis of lymphoma was present in seven (29%). The median CD4 + lymphocyte count was 112/mm3 (range, 19 to 791/mm3), and 17 patients (71%) had CD4+ lymphocytes less than 200/mm3. The majority (14 patients or 58%) had received no antiretroviral therapy before the diagnosis of lymphoma, while 10 patients (42%) had previously received HAART, for a median duration of 7 months before lymphoma diagnosis. The median HIV-1 RNA level in plasma was 93,650 copies/mL in the 20 patients with detectable virus (range, 1,005 to 4,090,000 copies/mL), while four patients had nondetectable viral load in plasma. All patients received antiretroviral therapy while on chemotherapy, with specific regimens determined by individual patient need (Table 2). Twenty patients were taking a HAART regimen that included a protease inhibitor, while four were taking non–PI-containing HAART regimens.
No patient experienced a dose-limiting toxicity at any of the three planned dose levels of Myocet, and CRs were seen at all dose levels. As the higher dose levels were associated with relatively greater myelosuppression, doses of Myocet were reduced to 50 mg/m2 for the formal phase II component of the trial, to which 14 patients were accrued. Granulocyte colony-stimulating factor was used in all patients and in 69% (73 of 107) of cycles. In all dose levels, neutropenia was the most common toxicity encountered, with grade 3 neutropenia as the maximal toxicity in 12% of patients, and grade 4 neutropenia in 18 patients (75%). Febrile neutropenia occurred in three patients (13%), while neutropenic sepsis was documented in two patients (8%). Opportunistic infections occurred in four patients (17%), including Pneumocystis carinii pneumonia (PCP) in two patients, aspergillosis and CMV pneumonitis in one patient, and disseminated strongyloides in one patient. Although all patients in the study were given PCP prophylaxis, both patients who developed PCP had lack of control of underlying HIV infection despite HAART, and they entered study with CD4 cell counts of 57/mm3 and 53/mm3. Similarly, the patient with disseminated strongyloides also lacked control of his HIV infection despite HAART. Specific toxicity data are presented in Table 3.
In terms of potential cardiac toxicity, LVEF was obtained at baseline and at study termination in 19 patients. No patient developed a decline in LVEF to below normal (45%). Fourteen patients had no significant change in LVEF over time, while 5 patients (26%) experienced a 10% or greater decline, though their LVEF values still remained within normal range. None of these five patients had any signs or symptoms of cardiac dysfunction, and the values returned to baseline levels in the two patients who had follow-up cardiac studies performed, 3 months after completion of chemotherapy. Complete remission of lymphoma was documented in 18 patients (75%), while partial response was seen in three (13%), for an overall objective response rate of 88%. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Relapse of lymphoma occurred in four complete responders, and progressive disease occurred in all three partial responders. Two of the relapsing complete responders relapsed with brain as a new site of disease. Both of these patients had received prior intrathecal cytarabine prophylaxis; one had marrow involvement at diagnosis. The other two complete responders, and all three partial responders experienced relapse of lymphoma at initial sites of disease. Twenty patients were assessable for determination of virologic response to HAART; two patients died of progressive lymphoma; and two died of HIV-associated complications before the planned repeat viral assessments. Sustained viral control was achieved in eight patients (40%), while transient viral control was documented in five patients (25%). HAART failed to control the HIV viral load in seven patients (35%). The relationship between response to chemotherapy and the virologic response to HAART is demonstrated in Table 4. There was no statistically significant relationship between virologic control and CR to chemotherapy. Thus, eight assessable patients with sustained viral control attained CR, while nine assessable patients with only transient or no viral control also achieved CR. Of interest, however, relapses tended to occur more frequently in patients without viral control (one of eight patients with viral control v six of 12 with transient or no viral control [P = .09]). Moreover, no assessable patient with HIV viral control has died to date, compared with six of 12 patients with transient or no virologic control (P = .017).
The relationship between tissue staining for P-gp associated with MDR-1 gene expression and response to chemotherapy is presented in Table 5. There was no statistically significant relationship between the presence of glycoprotein 170 in lymphoma tissue, and the likelihood of attaining complete remission with this Myocet-containing regimen.
In an attempt to ascertain those factors associated with attainment of CR to chemotherapy, univariate analysis revealed that elevated LDH level was of borderline significance (P = .07) in predicting decreased likelihood of attaining CR. No other factor was shown to be of significance (Table 6). Multivariate analysis could not be performed with validity, due to small numbers of patients enrolled and the fact that the majority of patients (75%) attained CR.
To date, the median overall survival has not yet been reached and is now in excess of 13.4 months (range, 1.7 to 46.9+; Fig 1). At 1 year from start of therapy, the overall survival was 58%. Nine patients (38%) had been followed up and were alive 2 years from the start of therapy. To date, 10 patients (42%) have died. This group was composed of four patients who died of either progressive lymphoma (two patients) or AIDS (two patients), and who were, therefore, not assessable for follow-up assessment of viral response, as well as all six with a documented failure of HIV viral control. On univariate analysis, the only factor shown to be statistically associated with decreased survival was lack of control of the HIV-1 viral load, though trends were seen with CD4 cells less than 100/mm3, history of prior AIDS, and elevated LDH levels. Multivariate models could not be constructed owing to small numbers of patients analyzed (Table 7).
The current prospective, phase I/II trial has demonstrated that substitution of the liposomal doxorubicin, Myocet, for doxorubicin in the standard CHOP regimen is feasible and effective in patients with newly diagnosed AIDS-related lymphoma, resulting in a complete remission rate of 75%, with durable remissions in the majority. Furthermore, while use of CHOP or moderate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone (m-BACOD) has been associated with a statistically decreased response rate in newly diagnosed patients whose lymphoma tissue expresses MDR-1,17 the current regimen was equally effective in both MDR-1–positive and -negative cases. It is possible that the efficacy of this regimen is related to the ability of liposome-encapsulated doxorubicin to overcome excessive drug efflux due to P-gp (MDR-1) overexpression.21,22 This area may be of special concern to patients with AIDS-related lymphoma, as protease inhibitors, one of the major components of HAART therapy, and efavirenz, a non-nucleoside reverse transcriptase inhibitor, are known substrates for MDR-1, capable of inducing MDR-1 expression.30-33 It is also possible that protease inhibitors could have a beneficial effect in terms of doxorubicin efflux from cells. Thus, in vitro data have shown that protease inhibitors may compete with other substrates for P-gp binding, albeit weakly, thus serving to decrease doxorubicin efflux from tumor cells through this mechanism.30 Recently, Little et al34 from the National Cancer Institute tested a novel 96-hour infusional regimen of etoposide, doxorubicin, and vincristine, with oral prednisone, and bolus, dose-adjusted cyclophosphamide (EPOCH regimen) in 39 patients with newly diagnosed AIDS-related lymphoma. HAART therapy was withheld during the 6 monthly cycles of EPOCH, and was reinstituted on completion of chemotherapy. Results were impressive, with an overall complete remission rate of 74%, a relapse-free survival of 92%, and an overall survival of 60% at 53 months. While median HIV viral load increased by 0.83 log10 during chemotherapy, and CD4 cells fell a median of 187 cells/mm3, these parameters returned to baseline values by 6 to 12 months after completion of chemotherapy. The use of continuous infusions of chemotherapy may overcome the drug efflux associated with MDR-1 expression, and may explain, in part, the efficacy of the EPOCH regimen. The current regimen, consisting of bolus dosing of all IV chemotherapy, may be easier to administer than a 96-hour continuous infusion, while still maintaining the ability to overcome MDR-1–induced drug resistance, through use of the liposomal doxorubicin.21,22 Antinori et al6 have shown that virologic response to chemotherapy was the only factor that correlated with response to CHOP chemotherapy in a group of 44 patients evaluated retrospectively. In the current prospective study, no statistically significant relationship was found between virologic response to HAART and antitumor response to the chemotherapy. This would be consistent with the data of Little et al, in whom impressive antilymphoma responses were achieved, in the setting of worsening viral and immunologic parameters.34 It would thus seem apparent that virologic control of HIV during the period of chemotherapy administration is not a requisite for optimal antitumor response. Of note, however, control of the underlying HIV does seem important in terms of overall survival, as has been well documented in numerous studies of HIV infection per se,8,9 and in patients with AIDS-related lymphoma and Hodgkin's disease as well.5-7 This would be consistent with our own results, demonstrating an increased number of deaths among AIDS-lymphoma patients who did not achieve virologic control with HAART. The optimal timing for institution of HAART in patients with AIDS-lymphoma is controversial at this time. While several investigators have shown a survival advantage to the use of concomitant HAART and chemotherapy,5-7 others have not.35,36 Thus, in Little's study of EPOCH, HAART therapy was instituted 6 days after the completion of all chemotherapy, resulting in a return to baseline virologic and immunologic parameters within 6 to 12 months.34 Nonetheless, opportunistic infections occurred in three patients within 3 months of the discontinuation of chemotherapy, before immunologic and/or virologic recovery. As demonstrated by the Little et al study, as well as the current data, although virologic control may not be mandatory for optimal antilymphoma effect, its use is clearly important in terms of preventing progression to frank AIDS or to death. Further study will be required to determine the optimal timing for institution or reinstitution of antiretroviral therapy in patients receiving chemotherapy for AIDS-related lymphoma. The current regimen was associated with significant myelosuppression, resulting in grade 4 neutropenia in 75% of patients, neutropenic fever in 12%, and neutropenic sepsis in 8%. Nonetheless, only one patient died of neutropenic sepsis (4%). Furthermore, no patient experienced grade 4 thrombocytopenia, and the regimen was generally well tolerated. The hematologic toxicity of Myocet, when substituted for doxorubicin in the CHOP regimen, seems quite similar to that previously reported with low-dose or standard-dose m-BACOD or CHOP.1,2,37 Of importance, mucositis was mild (grade 1 or 2) and occurred in only 21%. Further, no patient experienced clinical evidence of cardiac toxicity or a fall in LVEF to below normal range. While prospective in design, the current study is small, consisting of only 24 patients, which is insufficient to perform valid multivariate analysis on those factors predictive of response or survival. Nonetheless, all patients were carefully evaluated and followed up, all pathologic biospies were centrally reviewed, and all patients were considered in this intent-to-treat analysis. Furthermore, the patients accrued had far advanced and poor-risk lymphomatous disease, with a median CD4 lymphocyte count of only 112/mm3, and a median age of 43 years, which is considered "elderly" and is associated with poor prognosis in patients with AIDS-related lymphoma.38 Furthermore, the IPI score, which has been validated in patients with AIDS-lymphoma,39 indicated high-risk or high-intermediate–risk disease in 67%. Overall survival at 1 year was 58%. However, only nine patients (38%) have currently been followed up for as long as 2 years or beyond, making longer-term follow-up mandatory in terms of optimal evaluation of this regimen with respect to EPOCH, in which the median follow-up was approximately 5 years. These results must therefore be confirmed with larger, randomized trials. In summary, a CHOP-type regimen in which the doxorubicin was replaced by Myocet was shown to be highly effective in patients with newly diagnosed AIDS-lymphoma, with complete remission in 75%, and continuous, relapse-free survival in half of all treated patients (12 of 24 patients). The regimen was efficacious in inducing remission, irrespective of the tissue expression of MDR-1, or of the virologic response to HAART. This easily administered regimen warrants further study in larger numbers of patients.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Lauri Welles, Medeus Pharma Ltd. Performed contract work within the last 2 years: Alexandra M. Levine, Medeus Pharma Ltd.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25% of tumor cells staining positive for the C494 antigen were classified as MDR-1–positive. 
2 test for discrete data and a t test for continuous data.
